Project Summary Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease with an abysmal 5-year survival rate of < 9% for patients with PDAC. This sobering statistic indicates a need for novel therapeutic options. The vast majority (~90%) of PDAC patients carry a gain-of-function Kras mutation, which activates downstream signaling to drive tumorigenesis. One of these signaling molecules activated by Kras is IKKb. The cytokine, TNFa, is a well characterized molecule that also activates IKKb through phosphorylation of serine residues (S177 and S181) in its activation loop. Analyses of surgically resected tumor samples revealed the presence of TNFa in the tumor microenvironment of ~50% of all cancers. Consistently, in the tumor samples, a perfect correlation between the presence of TNFa and p-IKKb was observed. We analyzed PDAC samples obtained from the UNMC rapid autopsy pancreatic program and found elevated levels of p-IKKb in the PDAC cells of the primary tumor and liver mets when compared to adjacent normal tissue. A testable hypothesis derived from these observations was that p-IKKb exhibits oncogenic function in the presence of tumor associated mutations such as KrasG12D. To test this hypothesis, we generated mice that expressed constitutively activated IKKb (IKKbS177E,S181E) in the presence of KrasG12D. We observed that forced expression of IKKbS177E,S181E dramatically accelerated KrasG12D driven pancreatic cancer (median survival of < 2-weeks). Our cohort of KrasG12D; p53(-/-) mice became moribund ~ 5-6 months of age, which is consistent with reported studies. It is important to note that pancreas-specific IKKb(-/-) blocks the development of PDAC in KrasG12D mice. These studies suggest that p-IKKb exhibits potent oncogenic function and selective targeting of p-IKKb is a viable therapeutic option for PDAC. Traditionally, drugs are designed to bind / occupy their target and inactivate its function. The efficacy of the drug in this scenario correlates with the occupancy time of the drug on target (occupancy driven model). One of the challenges with this approach is dose-limiting toxicity, as it continues to be difficult to accurately predict the necessary dose required to inactivate the target in patients. An emerging event driven approach provides an alternate to the classical drug discovery approach. In this innovative model the drug functions as a catalyst that brings together the cellular protein destruction machinery to the target of interest. These catalysts are called PROteolysis Targeting Chimeras (PROTACs). They are composed of two ligands conjugated through a linker. One ligand of the PROTAC binds to the target of interest and the other ligand binds to an E3 ligase to facilitate the degradation of the target protein using the endogenous cellular machinery. The catalytic nature of PROTACs alleviates dose- limiting toxicity issues observed with traditional drugs. In this project we propose to apply the event driven model to develop PROTACs that will selectively degrade p-IKKb.